1. Virtual library screening (VLS) is a computational approach to rapidly identify new drug leads by assessing interactions between an in silico library of small molecules and the structure of a target macromolecule. 2. The VLS paradigm involves selecting a target protein structure, identifying its interaction site, docking diverse and synthetically accessible compounds from a library, scoring the interactions, and evaluating the highest scoring ligands. 3. During docking, different scoring functions are used to evaluate poses and rank ligands by energetically favorable interactions like hydrogen bonding and binding affinity scores.

1. S.Prasanth Kumar, Bioinformatician Virtual library screening (VLS) in the Drug Discovery Process Molecular Modeling & Drug Design S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA www.facebook.com/Prasanth Sivakumar FOLLOW ME ON ACCESS MY RESOURCES IN SLIDESHARE prasanthperceptron CONTACT ME [email_address]

2. Outlines of the Presentation Virtual Library Screening (VLS) VLS Paradigm Small molecule virtual libraries Target selection Binding site identification Docking Evaluation ORVIL-ORganic Virtual Library (MY WORK)

3. Virtual screening Virtual screening : a computational approach to assess the interaction of an in silico library of small molecules and the structure of a target macromolecule to rapidly identify new drug leads. Merits Computational Only high scoring ligands goes to assay Demerits Molecular Complexity/Diversity False Positives Synthesis Issue

4. VLS Paradigm Library Diverse Compounds, Synthetically accessible compounds Target Protein, Structure Determination Method ADME, Pharmacophore Interaction Site Docking Scoring & Evaluation Lead Optimization

5. Small Molecule Virtual Libraries Descriptors for chemical libraries (evaluate how much of chemical space is Sampled ) = diversity of a given library Structural properties: VDW, electrostatic, H-bond donor/acceptor = energetically favorable contacts Similarity/Dissimilarity Measures: Tanimoto Coefficient PubChem, CCD, ZINC, NCI, ACD, chEBI, Drug Bank

6. Tanimoto Coefficient N A is the number of features in A, N B is the number of features in B, and N AB is the number of features common to A and B. 5 4 = 4/(5+5-4) =0. 67

7. ADME/T properties Lipinski’s RO5 and Ghose et al, 1999 profiling for druglikeness e.g.QikProp,FAF-Drugs,ACDLabs Toxicity Analysis Toolkit a high possibility of complete absorption Topological polar surface area (TPSA) > 60 Å2 and < 140 Å2 An indicator of lipophilicity of a drug; high level of metabolic clearance by P450 enzymes of liver were expected logD pH (7.4) > 0 low level of toxicity, non-specific binding and possible oral administration logP value < 5 circumvent non-specific binding Hydrogen bond donors and acceptors < 5 and 10 better absorption and low level of allergic reactions MW < 500

8. Pharmacophore Mapping Ensemble of steric and electronic features required for interaction of ligand with biological target to triggers a biological response PHASE ReScore Daylight H HBD HBA R Query Database

9. Target selection Protein’s as Target : XRD, NMR, Homology Modeling PDB, Swiss Modeler, Modeller 9v7, WHATIF Human Estrogen Receptor (2P7Z)

10. Ligand Binding Site Modulate Protein’s Function SiteMap, CastP Binding Site Identification 3-Hydroxy Tamoxifen (Co-crystallized ligand)

11. The library must be docked into the target site and evaluated for goodness-of-fit. docking – the search for the conformation and configuration of the ligand in the binding site scoring – the evaluation of the interaction energy between the target and ligand Docking Docking of CDK6 Analogue Docking and in silico Bioavailability Analysis of CDK6 Flavonol Inhibitors and its Analogues for Acute Lymphoblastic Leukemia. (Under Review: Journal of Computational Intelligence in Bioinformatics) Glide,HEX 6,AutoDock,FlexX,DOCK 6.0,ArgusLab,GOLD

12. The scoring process evaluates and ranks each ligand pose in the target site Energetically Favorable Gibb’s Energy H-Bond Formation Other Scores The GScore is a combination of different parameters. GScore = 0.065 * van der Waal energy + 0.130 * Coulomb energy + Lipophilic term + Hydrogen-bonding term + Metal-binding term + Buried polar groups penalty + Freezing rotatable bonds penalty + Active site polar interactions. Scoring & Evaluation